The present invention relates to new aromatic derivatives, substituted by a ribose, their preparation process and their use as medicaments.
A subject of the invention is the compounds of formula (I): 
in which:
R1 represents a hydrogen atom, a hydroxyl radical, analkyl, alkenyl or alkynyl radical optionally interrupted by an oxygen, sulphur or nitrogen atom, containing up to 12 carbon atoms, linear, branched or cyclic, optionally substituted by one or more halogen atoms, one or more OH, C=N, NO2, 
radicals, in which Ra and Rb, identical or different, represent a hydrogen atom, an alkyl radicalcontaining up to 8 carbon atoms, or Ra and Rb form with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, or R1 represents an alkoxy radical containing up to 8 carbon atoms, optionally substituted by one or more of the substituents indicated above, or R1 represents an NRcRd radical in which Rc and Rd, identical or different, represent a hydrogen atom or an alkyl radical optionally interrupted by an oxygen, sulphur or nitrogen atom, containing up to 12 carbon atoms, optionally substituted by one or more of the substituents indicated above, or Rc and Rd form together with the nitrogen atom to which they are linked a heterocycle optionally containing another heteroatom chosen from nitrogen, sulphur or oxygen, X represents an oxygen atom, or an N-Nalk1 or NOalk2 radical in which alk1 and alk2 represent an alkyl radical containing up to 12 carbon atoms optionally substituted by one or more halogen atoms, by one or more 
radicals in which Re and Rf, identical to or different from each other represent a hydrogen atom, an alkyl radical containing up to 8 carbon atoms, optionally substituted, or Re and Rf are able to form together with the nitrogen atom to which they are joined a heterocycle which in addition is able to contain an oxygen, sulphur atom and another nitrogen atom,
R2 represents a hydrogen atom or a halogen atom,
R3 represents a hydrogen atom, an alkyl radical containing up to 8 carbon atoms or a halogen atom,
R4 represents an 
radical in which Rg and Rh, identical to or different from each other, represent a hydrogen atom, a linear, branched, cyclic alkyl radical containing up to 8 carbon atoms, an optionally substituted aryl or heteroaryl radical, or Rg and Rh form together with the nitrogen atom to which they are linked a heterocycle which is able to contain in addition an oxygen atom, sulphur atom and another nitrogen atom, or R4 represents an aryl or heteroaryl radical optionally substituted by one or more halogen atoms, one or more hydroxyl radicals, one or more alkyl or alkoxy radicals containing up to 8 carbon atoms,
R5 represents a hydrogen atom, an O-alkyl radical containing up to 4 carbon atoms,
R6 an alkyl or CH2xe2x80x94O-alkyl radical, in which alkyl represents an alkyl radical containing up to 8 carbon atoms,
R7 represents a hydrogen atom or an alkyl radical containing up to 8 carbon atoms, as well as their salts.
As examples of salts there can be mentioned sodium, potassium, lithium, calcium or magnesium salts, the salts obtained with nitrogenous bases such as trimethylamine, triethylamine, methylamine, propylamine, N,N-dimethyl ethanolamine and tris (hydroxymethyl) methylamine.
As examples of salts there can also be mentioned the salts formed with the following acids: acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulphonic, benzenesulphonic, p-toluenesulphonic, hydrochloric, hydrobromic, hydroiodic, sulphuric, phosphoric and especially stearic, ethylsuccinic or laurylsulphonic acids.
In the definition of the substituents:
the alkyl, alkenyl or alkynyl radical is preferably a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, cyclobutyl, cyclopentyl or cyclohexyl radical,
the halogen is preferably fluorine or chlorine, or bromine,
the aryl radical is preferably the phenyl radical,
the heterocyclic radical is preferably the pyrrolyl, pyrrolidinyl, pyridyl, pyrazinyl, pyrimidyl, piperidinyl, piperazinyl, quinuclidinyl, oxazolyl, isoxazolyl, morpholinyl, indolyl, imidazolyl, benzimidazolyl, triazolyl, thiazolyl, azetidinyl, aziridinyl radical.
Among the preferred compounds of the invention, there can be mentioned the compounds in which R2 represents a hydrogen atom, those in which R3 represents a methyl radical, those in which R6 represents a methyl radical, those in which R7 represents a hydrogen atom or a methyl radical and those in which R5 represents an OCH3 radical.
Quite especially a subject of the invention is the compounds of formula (I), in which R4 represents a 
radical, or also those in which R4 represents an NH-cyclopropyl radical.
Among the compounds of the invention, there can be quite particularly mentioned the compounds of formula (I) in which X represents an oxygen atom, those in which X represents an NOR radical, R representing an alkyl radical, optionally substituted by one or more halogen atoms and optionally interrupted by an oxygen, nitrogen, sulphur atom and optionally carrying an optionally substituted heterocyclic radical, for example those in which X represents an NOCH3 radical, there can also be mentioned as preferred compounds, the compounds of formula (I) in which R1 represents an alkyl radical optionally interrupted by an oxygen or sulphur atom, an O-alkyl radical, optionally interrupted by an oxygen or sulphur atom, an NH2 radical, for example the compounds in which R1 is a CH3, 
the compounds of formula (I) in which R1 represents a methyl or O-ethyl radical.
Among the preferred compounds of the invention, there can be quite especially mentioned the compounds whose preparation is given hereafter in the experimental part and in particular the following compounds:
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of 3-acetyl-7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexop yranosyl)oxy)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of ethyl 7((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxylate,
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-3-(1-(methoxyimino)-ethyl)-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-3-(ethoxyacetyl)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of 3-(cyclopropylcarbonyl)-7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)-oxy)-4-hydroxy-8-methyl-2H-1-benzopyran-2-one,
5-methyl-1H-pyrrole-2-carboxylic acid 3xe2x80x2-ester of 7-((6-deoxy-5-C-methyl-4-O-methyl-alpha-L-lyxo-hexopyranosyl)oxy)-4-hydroxy-8-methyl-2-oxo-2H-1-benzopyran-3-carboxamide,
The products of general formula (I) have a very good antibiotic activity on gram + bacteria such as staphylococci, streptococci, pneumococci, enterococci, listeria, anaerobes.
The compounds of the invention can therefore be used as medicaments in the treatment of infections caused by susceptible germs and in particular, in that of staphylococcia, such as staphylococcal septicemias, malignant staphylococcia of the face or skin, pyodermatitis, septic or suppurating wounds, boils, anthrax, phlegmons, erysipelas and acne, staphylococcia such as acute primary or post-influenzal angina, bronchopneumonia, pulmonary suppuration, streptococcia such as acute anginas, otitis, sinusitis, scarlet fever, pneumococcia such as pneumonia, bronchitis and diphteria. The products of the present invention are also active against infections caused by germs such as Haemophilus influenzae.
Therefore a subject of the invention is the compounds of formula (I) as medicaments.
A more particular subject of the invention is, as medicaments, the compounds indicated above as preferred compounds.
A subject of the invention is also the pharmaceutical compositions containing at least one of the medicaments defined above as active ingredient.
These compositions can be administered by buccal, rectal, parenteral route or by local route as a topical application on the skin and mucous membranes, but the preferred administration route is the buccal route. They can be solid or liquid and be presented in the pharmaceutical forms currently used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels; they are prepared according to the usual methods. The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
These compositions can also be presented in the form a powder intended to be dissolved extemporaneously in an appropriate vehicle, for example apyrogenic sterile water.
The dose administered is variable according to the illness treated, the patient in question, the administration route and the product considered. It can be, for example, comprised between 50 mg and 3000 mg per day by oral or injectable route, in an adult for the preferred products.
A subject of the invention is also a process characterized in that a compound of formula (II): 
in which R8 represents a free or blocked hydroxyl radical, Z represents hydrogen or a 
radical, X, R1, R2 and R3 retain their previous meaning, OR9 represents a free or blocked hydroxyl radical, is subjected to the action of a compound of formula (III): 
in which R5, R6 and R7 retain their previous meaning, ORxe2x80x24 represents a blocked hydroxyl radical, Rxe2x80x34 represents a hydrogen atom or Rxe2x80x24 and Rxe2x80x34 form together with the carbon atoms to which they are joined a cycle 
in order to obtain the compound of formula (IV): 
in which the substituents retain their previous meaning, then the compound of formula (IV) thus obtained is subjected to the following steps, in total or in part
release of the hydroxyl in position 4 after optional blocking of the hydroxyl of the sugar in alpha position of ORxe2x80x24,
if Z represents a hydrogen atom introduction of the 
radical after optional blocking of the hydroxyls which are able to react,
introduction of the 
radical by substitution of this radical by the Rxe2x80x24 radical,
modification of the X radical.
The starting products of the invention, namely, the products of formulae (II) and (III) are new products, examples of the preparation of these compounds are given hereafter in the experimental part.
The compounds of formula (IV) obtained during the implementation of the process of the invention are new.
Therefore a subject of the invention is, as new chemical products, the compounds of formulae (II), (III) and (IV).
In a preferred implementation of the process of the invention:
the reaction between the compounds of formulae (II) and (III) takes place in the presence of a dialkyl azodicarboxylate such as diethyl or diisopropyl azodicarboxylate,
the optional release of the hydroxyl in position 4 of the coumarin, is carried out by hydrogenolysis or by isomerization then hydrolysis,
the other protected hydroxyls are released by acid hydrolysis for example, in the presence of paratoluene sulphonic acid,
the introduction of the 
radical when Z represents hydrogen, is carried out by acylation then transposition,
the glycosylation takes place by Mitsunobu""s reaction.
the other modifications are carried out under standard conditions.
The following examples illustrate the invention without however limiting it.
STAGE A: phenylmethyl 6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranoside
A stream of hydrochloric acid gas is bubbled through a suspension containing 80 g of 6-deoxy 5-C-methyl-4-O-methyl-L-lyxohexopyranose and 400 ml of benzyl alcohol for 2 hours at 20xcx9c22xc2x0 C. 120 ml of demineralized water is added and 40 g of sodium carbonate is added, then 240 ml of ethyl acetate. After decanting and extracting with ethyl acetate, the organic phases are combined and washed with a saturated solution of sodium chloride. Followed by drying, separating, rinsing and distilling under agitation and under vacuum at 45xcx9c50 mb. The benzyl alcohol is distilled under vacuum at 2 mb. 118.8 g of a product is obtained which is purified by chromatography on silica eluting with a methylene chloride/methanol mixture (95-5). In this way 109.9 g of sought product is obtained.
STAGE B: phenylmethyl-2,3-O-carbonyl-6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranoside
67.5 g of 1,1-carbonyldiimidazole is added to a solution containing 109 g of the product prepared in Stage A and 1.1 l of dichloro-1-2-ethane. The reaction medium is taken to reflux for 2 hours. The temperature is returned to 20xcx9c22xc2x0 C. then the reaction medium is brought to dryness under reduced pressure at 25xcx9c30xc2x0 C. 200.8 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride-methanol mixture (99-1). 91.6 g of sought product is obtained.
I.R. Spectrum
The 2-1H-pyrrole used in Stage C was prepared as follows:
750 g of pure caustic potash is added to a suspension containing 5 l of ethylene glycol and 370 g of 2-carboxaldehyde pyrrole. Then 544 cm3 of 64% hydrazine hydrate is added over 30 minutes. The reaction medium is taken to reflux for 1 hour 30 minutes and 2 l of demineralized water is added then it is poured into a water-ice mixture. Extraction is carried out with methylene chloride, followed by drying, separating, rinsing and bringing to dryness. 270.3 g of product is obtained which is purified by distillation under pressure of 15 millibars. 227 g of sought product is collected.
Tbp=46xcx9c470xc2x0 C. under 15 millibars.
STAGE C: 3-(5-methyl-1H-pyrrole-2-carboxylate) of phenylmethyl-6-deoxy-5-C-methyl-4-O-methyl-L-lyxo-hexopyranoside
A solution containing 60.2 g of 2-methyl-1H-pyrrole in 460 ml of ethyl ether is added over one hour at 0xcx9c2xc2x0 C. to 248 ml of a 3M solution of methylmagnesium bromide in ether. The reaction medium is maintained under agitation at 0xcx9c2xc2x0 C. for 30 minutes and 460 cm3 of toluene dethiophene is added over 15 minutes. Agitation is carried out for 15 minutes at 0xc2x12xc2x0 C. and a solution of 91.3 g of the product prepared in Stage B and 460 ml of toluene dethiophene are introduced over 45 minutes. Agitation is maintained for 2 hours at 0xc2x12xc2x0 C. The reaction medium is poured into an aqueous solution of ammonium chloride, followed by decanting, extracting with ethyl acetate, washing, drying, rinsing and bringing to dryness under reduced pressure. 134.6 g of product is obtained which is purified by chromatography on silica eluting with a methylene chloride-acetone mixture (8-2), then (9-1). In this way the sought product is obtained.
STAGE D: 3-(5-methyl-1H-pyrrole-2-carboxylate) of 6-deoxy-5-C-methyl-4-O-methyl-L-lyxohexopyranose
14.7 of 10% palladium on activated carbon is added to a solution containing 72.4 g of the product prepared in Stage C and 1.45 l of denatured ethanol 100. The reaction medium is maintained under hydrogen pressure for 1 hour at 60xcx9c62xc2x0 C. The reaction medium is allowed to return to ambient temperature. Another 1.5 g of 10% palladium on activated carbon is added. Agitation is carried out under hydrogen pressure for 1 hour. The temperature is returned to 20xcx9c22xc2x0 C., followed by separating, filtering, rinsing, and after bringing to dryness, 57 g of sought product is obtained.
STAGE A: 1-[2-hydroxy-3-methyl-4-[(tetrahydro-2H-pyran-2-yl) oxy] phenyl ethanone
A mixture containing 200 g of 1-[2,4-dihydroxy-3-methyl] phenyl ethanone and 1.2 l of ethyl ether is cooled down to 8xc2x0 C. 200 ml of dihydro-2H-pyran and 1 g of PTSA are added. The reaction medium is left to return to ambient temperature. Agitation is carried out for 3 hours and 253 mg of PTSA is added. The product obtained is poured into 400 ml of a molar aqueous solution of potassium acid phosphate, followed by decanting, washing with water and drying. After evaporation 302.5 g of crude sought product is obtained which is purified thus: the product is diluted in 2 l of methylene chloride, the organic phase is washed with ammonium hydroxide diluted to one tenth, then with brine, dried, filtered and evaporated to dryness. 272.55 g of sought product is obtained.
STAGE B: 4-hydroxy-8-methyl-7-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-1-benzopyran-2-one
A mixture containing 750 ml of toluene, 129.9 g of the product prepared in Stage A and 126 ml of diethyl carbonate in 620 ml of toluene is heated to 90xc2x0 C. 52 g of sodium hydride at 55% in oil is added while maintaining the temperature at 90xc2x0 C. The reaction medium is maintained under agitation at 90xc2x0 C. and left to return to ambient temperature. 10 ml of ethyl alcohol is added, followed by separating and rinsing with ethyl ether, then separating. The whole is poured into 1 l of a molar aqueous solution of sodium acid phosphate, followed by separating and rinsing with water, with acetone and with ether. A product is obtained which is dried at 50xc2x0 C. in the presence of P2O5. 141.89 g of sought product is obtained.
STAGE C: 8-methyl-4-(2-propenyloxy)-7-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-1-benzopyran-2-one
9.45 ml of diethyl azocarboxylate is added at 0xc2x0 C. to a mixture containing 13.814 g of the product prepared in the preceding stage, 4.07 ml of allyl alcohol, 15.74 g of triphenylphosphosphine and 150 ml of dichloromethane. The reaction medium is maintained under agitation for 15 minutes at 0xc2x0 C. then for 2 hours at ambient temperature. Another 5.25 g of triphenylphosphine, 1.36 ml of allyl alcohol and 3.15 ml of diethyl azodicarboxylate are added. The reaction medium is agitated for 2 hours at ambient temperature. After concentration, the product obtained is chromatographed on silica eluting with a hexane-ethyl acetate mixture (3-1). 7.85 g of product is obtained.
STAGE D: 7-hydroxy-8-methyl-4-(2-propenyloxy)-2H-1-benzopyran-2-one
A mixture containing 7.80 g of the product prepared in the preceding stage in 150 ml of tetrahydrofuran to which 100 ml of a 1M solution HCl has been added is agitated for 6 hours at ambient temperature. Then a saturated solution of sodium chloride is added and extraction is carried out with ethyl acetate. The organic phase is dried over magnesium sulphate and concentrated to dryness. After drying 4.40 g of sought product is obtained.
rf=0.26 hexane ethyl acetate (1-1).